The fibrillin-1 RGD motif posttranscriptionally regulates ERK1/2 signaling and fibroblast proliferation via miR-1208

FASEB J. 2021 May;35(5):e21598. doi: 10.1096/fj.202100282R.


Fibrillin-1 is an extracellular matrix protein which contains one conserved RGD integrin-binding motif. It constitutes the backbone of microfibrils in many tissues, and mutations in fibrillin-1 cause various connective tissue disorders. Although it is well established that fibrillin-1 interacts with several RGD-dependent integrins, very little is known about the associated intracellular signaling pathways. Recent published evidence identified a subset of miRNAs regulated by fibrillin-1 RGD-cell adhesion, with miR-1208 among the most downregulated. The present study shows that the downregulated miR-1208 controls fibroblast proliferation. Inhibitor experiments revealed that fibrillin-1 RGD suppressed miR-1208 expression via c-Src kinase and the downstream JNK signaling. Bioinformatic prediction and experimental target sequence validation demonstrated four miR-1208 binding sites on the ERK2 mRNA and one on the MEK1 mRNA. ERK2 and MEK1 are critical proliferation-promoting kinases. Decreased miR-1208 levels elevated the total and phosphorylated ERK1/2 and MEK1/2 protein levels and the phosphorylated to total ERK1/2 ratio. Together, the data demonstrate a novel outside-in signaling mechanism explaining how fibrillin-1 RGD-cell binding regulates fibroblast proliferation.

Keywords: ERK1/2 signaling; RGD; fibrillin-1; fibroblasts; miR-1208; proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation
  • Cells, Cultured
  • Fibrillin-1 / genetics
  • Fibrillin-1 / metabolism*
  • Fibroblasts / cytology*
  • Fibroblasts / metabolism
  • Humans
  • MicroRNAs / genetics*
  • Mitogen-Activated Protein Kinase 1 / genetics*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / genetics*
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Oligopeptides / genetics
  • Oligopeptides / metabolism*
  • RNA Processing, Post-Transcriptional*


  • FBN1 protein, human
  • Fibrillin-1
  • MicroRNAs
  • Oligopeptides
  • arginyl-glycyl-aspartic acid
  • MAPK1 protein, human
  • MAPK3 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3

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